Background:The primary cause of treatment failure in patients with refractory or relapsed B-cell non-Hodgkin lymphoma(r/r B-NHL)is resistance to current therapies,and therapy-induced senescence(TIS)stands out as a cru...Background:The primary cause of treatment failure in patients with refractory or relapsed B-cell non-Hodgkin lymphoma(r/r B-NHL)is resistance to current therapies,and therapy-induced senescence(TIS)stands out as a crucial mechanism contributing to tumor drug resistance.Here,we analyzed SENEX/Rho GTPase Activating Protein 18(ARHGAP18)expression and prognostic significance in doxorubicin-induced B-NHL-TIS model and r/r B-NHL patients,investigating its target in B-NHL cell senescence and the effect of combining specific inhibitors on apoptosis resistance in B-NHL-TIS cells.Methods:Raji cells were transfected with the human SENEX shRNA recombinant lentiviral vector(Sh-SENEX)and the empty vector negative(NC)to construct a stable transfection cell line with knockdown of SENEX.Effect of SENEX-silencing on B-NHL-TIS formation,cell function and cell cycle-related pathways was analyzed.Using doxorubicin(DOX)-inducible senescent B-NHL cells combined with the specific cyclin dependent kinase 4/6(CDK4/6)inhibitor Palbociclib to observe that blocking CDK4/6 effects on TIS formation.SENEX expression of 21 B-NHL patients and 8 healthy controls were analyzed by qRT-PCR,and the correlation between its expression and clinical indicators were evaluated.Results:The downregulation of SENEX expression promotes G1-S phase transition and apoptosis while inhibiting cell proliferation,collectively suppressing the formation of TIS in B-NHL.Blockade of CDK4/6 promotes the DOX-induced G1 phase arrest to enhance TIS formation in B-NHL cells which can reverse the regulatory effect of silencing SENEX on B-NHL cell cycle regulation and senescence.The expression levels of SENEX were notably elevated in B-NHL patients compared to healthy controls,and Elevated expression levels of SENEX were associated with poor prognosis of B-NHL patients.Conclusions:SENEX enhances apoptosis resistance in B-NHL by inhibiting CDK4/6,thereby preventing G1-S phase transition and promoting TIS formation.展开更多
We describe a 70-year-old female patient with diffuse large B-cell lymphoma of the cerebellum;she received resection of a left atrial myxoma five months ago.To the best of our knowledge,to date no association of atria...We describe a 70-year-old female patient with diffuse large B-cell lymphoma of the cerebellum;she received resection of a left atrial myxoma five months ago.To the best of our knowledge,to date no association of atrial myxoma with the malignant cerebellar diffuse large B-cell lymphoma has been reported in the literature,except for high level of interleukin-6 (IL-6) in the serum under both conditions.IL-6 as a pro-inflammatory cytokine has been shown to be associated with tumor progression,including inhibition of cancer cell apoptosis and stimulation of angiogenesis.IL-6 concentrations may provide possible aetiological links between atrial myxoma and cerebellar diffuse large B-cell lymphoma in our case.展开更多
Lymphomas may be induced by the systemic immunosuppressive therapies used to treat psoriasis,such as ciclosporin,methotrexate and tumour necrosis factor(TNF)-α blockers.The biologic agents currently used in psoriasis...Lymphomas may be induced by the systemic immunosuppressive therapies used to treat psoriasis,such as ciclosporin,methotrexate and tumour necrosis factor(TNF)-α blockers.The biologic agents currently used in psoriasis include alefacept,efalizumab,and the TNF-α antagonists etanercept,infliximab,and adalimumab.Infections and cancer are the main possible consequences of intended or unexpected immunosuppression.We report a 59-year-old man with a history of severe psoriasis vulgaris treated with traditional immunosuppressant drugs followed by anti-TNF-α therapy;the patient was firstly hospitalized for an acute cholestatic toxic hepatitis,which we supposed to be related to adalimumab.The first liver biopsy showed active disease with severe hepatocellular damage caused by heavy lymphocytes infiltrate in portal tracts at in the interface with a not conclusive diagnosis of lymphoproliferative disease.The correct diagnosis of T cell/histiocyte-rich large B cell lymphoma(T/HRBCL) was only reached through a gastric biopsy and a second liver biopsy.T/HRBCL is an uncommon morphologic variant of diffuse large B-cell lymphoma not described until now in psoriatic patients receiving immunosuppressive biologic agents.In psoriatic patients,treated with biologic immunosuppressive agents,the suspect of abdominal lymphoma should always be included as differential diagnosis.Abdominal ultrasound evaluation need therefore to be included in the pretreatment screening as in the follow-up surveillance.展开更多
【指示性摘要】IL-6由肿瘤细胞自分泌,与肿瘤侵袭性密切相关;TNF-α在机体肿瘤免疫应答中起到了重要作用,可引起肿瘤细胞坏死,且可诱导IL-6的表达;IFN-γ具有抗病毒,抗肿瘤和免疫调控的作用;IL-10具有双向免疫调节作用,在肿瘤环境中对...【指示性摘要】IL-6由肿瘤细胞自分泌,与肿瘤侵袭性密切相关;TNF-α在机体肿瘤免疫应答中起到了重要作用,可引起肿瘤细胞坏死,且可诱导IL-6的表达;IFN-γ具有抗病毒,抗肿瘤和免疫调控的作用;IL-10具有双向免疫调节作用,在肿瘤环境中对免疫应答具有负向调节作用,同时也能发挥刺激作用。上述细胞因子在弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)的发生发展中或起到协同作用,并可能作为DLBCL诊断及预后的指标。展开更多
Background Studies have shown that the drug resistance of gastric cancer cells can be modulated by abnormal expression of microRNAs （miRNAs）.We investigated the role of miR-503 in the development of cisplatin resist...Background Studies have shown that the drug resistance of gastric cancer cells can be modulated by abnormal expression of microRNAs （miRNAs）.We investigated the role of miR-503 in the development of cisplatin resistance in human gastric cancer cell lines.Methods MiR-503 expression was measured by quantitative real-time PCR.MTT （3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide） and clonogenic assays were used to examine changes in cell viability and the drug resistance phenotype of cancer cells associated with upregulation or downregulation of the miRNA.A dual-luciferase activity assay was used to verify target genes of miR-503.Immunohistochemistry,Western blotting analysis,and a flow cytometric apoptosis assay were used to elucidate the mechanism by which miR-503 modulates drug resistance in cancer cells.Results MiR-503 was significantly downregulated in gastric cancer tissues and several gastric cancer cell lines.Additionally,downregulation of miR-503 in the cisplatin （DDP）-resistant gastric cancer cell line SGC7901/DDP was concurrent with the upregulation of insulin-like growth factor-1 receptor （IGF1R） and B-cell lymphoma 2 （BCL2） expression compared with the parental SGC7901 cell line.An in vitro drug sensitivity assay showed that overexpression of miR-503 sensitized SGC7901/DDP cells to cisplatin.The luciferase activity of reporters driven by IGF1R and BCL2 3＇-untranslated regions in SGC7901/DDP cells suggested that IGF1R and BCL2 were both direct target genes of miR-503.Enforced miR-503 expression in SGC7901/DDP cells reduced expression of the target proteins,inhibited proliferation,and sensitized the cells to DDP-induced apoptosis.Conclusion Our findings suggest that hsa-miR-503 modulates cisplatin resistance of human gastric cancer cells at least in part by targeting IGF1R and BCL2.展开更多
基金This work was supported by the Major Subject of Science and Technology of Anhui Province(Grant Number:201903a07020030).
文摘Background:The primary cause of treatment failure in patients with refractory or relapsed B-cell non-Hodgkin lymphoma(r/r B-NHL)is resistance to current therapies,and therapy-induced senescence(TIS)stands out as a crucial mechanism contributing to tumor drug resistance.Here,we analyzed SENEX/Rho GTPase Activating Protein 18(ARHGAP18)expression and prognostic significance in doxorubicin-induced B-NHL-TIS model and r/r B-NHL patients,investigating its target in B-NHL cell senescence and the effect of combining specific inhibitors on apoptosis resistance in B-NHL-TIS cells.Methods:Raji cells were transfected with the human SENEX shRNA recombinant lentiviral vector(Sh-SENEX)and the empty vector negative(NC)to construct a stable transfection cell line with knockdown of SENEX.Effect of SENEX-silencing on B-NHL-TIS formation,cell function and cell cycle-related pathways was analyzed.Using doxorubicin(DOX)-inducible senescent B-NHL cells combined with the specific cyclin dependent kinase 4/6(CDK4/6)inhibitor Palbociclib to observe that blocking CDK4/6 effects on TIS formation.SENEX expression of 21 B-NHL patients and 8 healthy controls were analyzed by qRT-PCR,and the correlation between its expression and clinical indicators were evaluated.Results:The downregulation of SENEX expression promotes G1-S phase transition and apoptosis while inhibiting cell proliferation,collectively suppressing the formation of TIS in B-NHL.Blockade of CDK4/6 promotes the DOX-induced G1 phase arrest to enhance TIS formation in B-NHL cells which can reverse the regulatory effect of silencing SENEX on B-NHL cell cycle regulation and senescence.The expression levels of SENEX were notably elevated in B-NHL patients compared to healthy controls,and Elevated expression levels of SENEX were associated with poor prognosis of B-NHL patients.Conclusions:SENEX enhances apoptosis resistance in B-NHL by inhibiting CDK4/6,thereby preventing G1-S phase transition and promoting TIS formation.
文摘We describe a 70-year-old female patient with diffuse large B-cell lymphoma of the cerebellum;she received resection of a left atrial myxoma five months ago.To the best of our knowledge,to date no association of atrial myxoma with the malignant cerebellar diffuse large B-cell lymphoma has been reported in the literature,except for high level of interleukin-6 (IL-6) in the serum under both conditions.IL-6 as a pro-inflammatory cytokine has been shown to be associated with tumor progression,including inhibition of cancer cell apoptosis and stimulation of angiogenesis.IL-6 concentrations may provide possible aetiological links between atrial myxoma and cerebellar diffuse large B-cell lymphoma in our case.
文摘Lymphomas may be induced by the systemic immunosuppressive therapies used to treat psoriasis,such as ciclosporin,methotrexate and tumour necrosis factor(TNF)-α blockers.The biologic agents currently used in psoriasis include alefacept,efalizumab,and the TNF-α antagonists etanercept,infliximab,and adalimumab.Infections and cancer are the main possible consequences of intended or unexpected immunosuppression.We report a 59-year-old man with a history of severe psoriasis vulgaris treated with traditional immunosuppressant drugs followed by anti-TNF-α therapy;the patient was firstly hospitalized for an acute cholestatic toxic hepatitis,which we supposed to be related to adalimumab.The first liver biopsy showed active disease with severe hepatocellular damage caused by heavy lymphocytes infiltrate in portal tracts at in the interface with a not conclusive diagnosis of lymphoproliferative disease.The correct diagnosis of T cell/histiocyte-rich large B cell lymphoma(T/HRBCL) was only reached through a gastric biopsy and a second liver biopsy.T/HRBCL is an uncommon morphologic variant of diffuse large B-cell lymphoma not described until now in psoriatic patients receiving immunosuppressive biologic agents.In psoriatic patients,treated with biologic immunosuppressive agents,the suspect of abdominal lymphoma should always be included as differential diagnosis.Abdominal ultrasound evaluation need therefore to be included in the pretreatment screening as in the follow-up surveillance.
文摘【指示性摘要】IL-6由肿瘤细胞自分泌,与肿瘤侵袭性密切相关;TNF-α在机体肿瘤免疫应答中起到了重要作用,可引起肿瘤细胞坏死,且可诱导IL-6的表达;IFN-γ具有抗病毒,抗肿瘤和免疫调控的作用;IL-10具有双向免疫调节作用,在肿瘤环境中对免疫应答具有负向调节作用,同时也能发挥刺激作用。上述细胞因子在弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)的发生发展中或起到协同作用,并可能作为DLBCL诊断及预后的指标。
基金This research was supported by grants from the National Natural Science Foundation of China （No.81201705 and No.81201796） and the Natural Science Foundation of Jiangsu Province （No.BK2012442）.
文摘Background Studies have shown that the drug resistance of gastric cancer cells can be modulated by abnormal expression of microRNAs （miRNAs）.We investigated the role of miR-503 in the development of cisplatin resistance in human gastric cancer cell lines.Methods MiR-503 expression was measured by quantitative real-time PCR.MTT （3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide） and clonogenic assays were used to examine changes in cell viability and the drug resistance phenotype of cancer cells associated with upregulation or downregulation of the miRNA.A dual-luciferase activity assay was used to verify target genes of miR-503.Immunohistochemistry,Western blotting analysis,and a flow cytometric apoptosis assay were used to elucidate the mechanism by which miR-503 modulates drug resistance in cancer cells.Results MiR-503 was significantly downregulated in gastric cancer tissues and several gastric cancer cell lines.Additionally,downregulation of miR-503 in the cisplatin （DDP）-resistant gastric cancer cell line SGC7901/DDP was concurrent with the upregulation of insulin-like growth factor-1 receptor （IGF1R） and B-cell lymphoma 2 （BCL2） expression compared with the parental SGC7901 cell line.An in vitro drug sensitivity assay showed that overexpression of miR-503 sensitized SGC7901/DDP cells to cisplatin.The luciferase activity of reporters driven by IGF1R and BCL2 3＇-untranslated regions in SGC7901/DDP cells suggested that IGF1R and BCL2 were both direct target genes of miR-503.Enforced miR-503 expression in SGC7901/DDP cells reduced expression of the target proteins,inhibited proliferation,and sensitized the cells to DDP-induced apoptosis.Conclusion Our findings suggest that hsa-miR-503 modulates cisplatin resistance of human gastric cancer cells at least in part by targeting IGF1R and BCL2.
